Lachlan J. Smith, John T. Martin, Makarand V. Risbud
The sixth biennial ORS PSRS International Spine Research Symposium was held from November 6 to 10, 2022, at Skytop Lodge in northeastern Pennsylvania, USA. Organized jointly by the Orthopaedic Research Society and the Philadelphia Spine Research Society, the symposium attracted more than 200 participants from 15 different countries who came together to share the latest advances in basic and preclinical spine research. Following the symposium, selected participants were invited to submit full-length manuscripts to this special issue of JOR Spine.
{"title":"Advancing basic and preclinical spine research: Highlights from the ORS PSRS 6th International Spine Research Symposium","authors":"Lachlan J. Smith, John T. Martin, Makarand V. Risbud","doi":"10.1002/jsp2.1308","DOIUrl":"https://doi.org/10.1002/jsp2.1308","url":null,"abstract":"<p>The sixth biennial ORS PSRS International Spine Research Symposium was held from November 6 to 10, 2022, at Skytop Lodge in northeastern Pennsylvania, USA. Organized jointly by the Orthopaedic Research Society and the Philadelphia Spine Research Society, the symposium attracted more than 200 participants from 15 different countries who came together to share the latest advances in basic and preclinical spine research. Following the symposium, selected participants were invited to submit full-length manuscripts to this special issue of <i>JOR Spine</i>.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"6 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139042038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chien-Hsiung Lo, Yu-Hua Dean Fang, Jing-Yao Wang, Tzu-Ping Yu, Hao-Chun Chuang, Yuan-Fu Liu, Chao-Jui Chang, Cheng-Li Lin
Background
The sagittal imbalance (SI) of spine triggers compensatory mechanisms (CMs) of lower extremity (LE) to restore trunk balance. These CMs can cause long-period stress on the femur and may possibly alter the femoral morphology. This cross-sectional observational study aimed to answer the following questions: (a) Do SI subjects exhibit greater femoral bowing compared to subjects with sagittal balance? (b) Are there associations between femoral bowing and CMs of LE in SI subjects?
Methods
Subjects who underwent biplanar full body radiographs with the EOS imaging system between January 2016 and September 2021 were recruited. Sagittal parameters included T1-pelvic angle (TPA), pelvic incidence (PI), pelvic tilt (PT), sacral slope, lumbar lordosis (LL), PI-LL, and PT/PI ratio. LE parameters were femoral obliquity angle (FOA), knee flexion angle (KA), and ankle dorsiflexion angle. Femoral bowing was quantified as 3D radius of femoral curvature (RFC). Associations between 3D RFC and the radiographic parameters were analyzed.
Results
A total of 105 subjects were included, classified into balance group (TPA < 14°, n = 40), SI group (TPA ≥ 14° and KA <5°, n = 30), and SI with knee flexion group (TPA ≥ 14° and KA ≥ 5°, n = 35). 3D RFC was significantly lower in SI with knee flexion group compared to the other two groups (both p < 0.001). Stepwise linear regression showed that age, SI and knee flexion, femoral length (FL), FOA, and KA were independent predictors for 3D RFC.
Conclusion
Greater femoral bowing is observed in subjects with SI and knee flexion compared to the balanced population. CM parameters, including KA and FOA, are associated with 3D RFC. Further longitudinal study is needed to investigate the cause-and-effect relationship between SI, CMs of LE, and femoral bowing.
脊柱的矢状失衡（SI）会触发下肢（LE）的补偿机制（CM），以恢复躯干平衡。这些代偿机制会对股骨造成长期压力，并可能改变股骨形态。这项横断面观察性研究旨在回答以下问题：（a）与矢状平衡受试者相比，SI 受试者是否表现出更大的股骨弯曲？(b) SI 受试者的股骨弯曲与 LE 的 CMs 之间是否存在关联？矢状面参数包括 T1-骨盆角 (TPA)、骨盆入射角 (PI)、骨盆倾斜 (PT)、骶骨斜度、腰椎前凸 (LL)、PI-LL 和 PT/PI 比值。LE参数为股骨倾斜角（FOA）、膝关节屈曲角（KA）和踝关节背屈角。股骨弯曲以三维股骨曲率半径（RFC）量化。共纳入105名受试者，分为平衡组（TPA<14°，n=40）、SI组（TPA≥14°且KA<5°，n=30）和膝关节屈曲SI组（TPA≥14°且KA≥5°，n=35）。与其他两组相比，膝关节屈曲的 SI 组的 3D RFC 明显较低（均 p <0.001）。逐步线性回归显示，年龄、SI和膝关节屈曲度、股骨长度（FL）、FOA和KA是三维RFC的独立预测因子。包括 KA 和 FOA 在内的 CM 参数与 3D RFC 相关。需要进一步的纵向研究来探讨SI、LE的CMs和股骨弯曲之间的因果关系。
{"title":"Associations between femoral 3D curvature and sagittal imbalance of spine","authors":"Chien-Hsiung Lo, Yu-Hua Dean Fang, Jing-Yao Wang, Tzu-Ping Yu, Hao-Chun Chuang, Yuan-Fu Liu, Chao-Jui Chang, Cheng-Li Lin","doi":"10.1002/jsp2.1305","DOIUrl":"10.1002/jsp2.1305","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The sagittal imbalance (SI) of spine triggers compensatory mechanisms (CMs) of lower extremity (LE) to restore trunk balance. These CMs can cause long-period stress on the femur and may possibly alter the femoral morphology. This cross-sectional observational study aimed to answer the following questions: (a) Do SI subjects exhibit greater femoral bowing compared to subjects with sagittal balance? (b) Are there associations between femoral bowing and CMs of LE in SI subjects?</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Subjects who underwent biplanar full body radiographs with the EOS imaging system between January 2016 and September 2021 were recruited. Sagittal parameters included T1-pelvic angle (TPA), pelvic incidence (PI), pelvic tilt (PT), sacral slope, lumbar lordosis (LL), PI-LL, and PT/PI ratio. LE parameters were femoral obliquity angle (FOA), knee flexion angle (KA), and ankle dorsiflexion angle. Femoral bowing was quantified as 3D radius of femoral curvature (RFC). Associations between 3D RFC and the radiographic parameters were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 105 subjects were included, classified into balance group (TPA < 14°, <i>n</i> = 40), SI group (TPA ≥ 14° and KA <5°, <i>n</i> = 30), and SI with knee flexion group (TPA ≥ 14° and KA ≥ 5°, <i>n</i> = 35). 3D RFC was significantly lower in SI with knee flexion group compared to the other two groups (both <i>p</i> < 0.001). Stepwise linear regression showed that age, SI and knee flexion, femoral length (FL), FOA, and KA were independent predictors for 3D RFC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Greater femoral bowing is observed in subjects with SI and knee flexion compared to the balanced population. CM parameters, including KA and FOA, are associated with 3D RFC. Further longitudinal study is needed to investigate the cause-and-effect relationship between SI, CMs of LE, and femoral bowing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139259605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bahar Shahidi, Bradley Anderson, Angel Ordaz, David B. Berry, Severin Ruoss, Vinko Zlomislic, R. Todd Allen, Steven R. Garfin, Mazda Farshad, Simon Schenk, Samuel R. Ward
Background
Lumbar spine pathology (LSP) is a common source of low back or leg pain, and paraspinal muscle in these patients demonstrates fatty and fibrotic infiltration, and cellular degeneration that do not reverse with exercise-based rehabilitation. However, it is unclear of this lack of response is due to insufficient exercise stimulus, or an inability to mount a growth response. The purpose of this study was to compare paraspinal muscle gene expression between individuals with LSP who do and do not undergo an acute bout of resistance exercise.
Methods
Paraspinal muscle biopsies were obtained from 64 individuals with LSP undergoing spinal surgery. Eight participants performed an acute bout of machine-based lumbar extension resistance exercise preoperatively. Gene expression for 42 genes associated with adipogenic/metabolic, atrophic, fibrogenic, inflammatory, and myogenic pathways was measured, and differential expression between exercised and non-exercised groups was evaluated for (a) the full cohort, and (b) an age, gender, acuity, and etiology matched sub-cohort. Principal components analyses were used to identify gene expression clustering across clinical phenotypes.
Results
The exercised cohort demonstrated upregulation of inflammatory gene IL1B, inhibition of extracellular matrix components (increased MMP3&9, decreased TIMP1&3, COL1A1) and metabolic/adipogenic genes (FABP4, PPARD, WNT10B), and downregulation of myogenic (MYOD, ANKRD2B) and atrophic (FOXO3) genes compared to the non-exercised cohort, with similar patterns in the matched sub-analysis. There were no clinical phenotypes significantly associated with gene expression profiles.
Conclusion
An acute bout of moderate-high intensity resistance exercise did not result in upregulation of myogenic genes in individuals with LSP. The response was characterized by mixed metabolic and fibrotic gene expression, upregulation of inflammation, and downregulation of myogenesis.
{"title":"Paraspinal muscles in individuals undergoing surgery for lumbar spine pathology lack a myogenic response to an acute bout of resistance exercise","authors":"Bahar Shahidi, Bradley Anderson, Angel Ordaz, David B. Berry, Severin Ruoss, Vinko Zlomislic, R. Todd Allen, Steven R. Garfin, Mazda Farshad, Simon Schenk, Samuel R. Ward","doi":"10.1002/jsp2.1291","DOIUrl":"10.1002/jsp2.1291","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lumbar spine pathology (LSP) is a common source of low back or leg pain, and paraspinal muscle in these patients demonstrates fatty and fibrotic infiltration, and cellular degeneration that do not reverse with exercise-based rehabilitation. However, it is unclear of this lack of response is due to insufficient exercise stimulus, or an inability to mount a growth response. The purpose of this study was to compare paraspinal muscle gene expression between individuals with LSP who do and do not undergo an acute bout of resistance exercise.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Paraspinal muscle biopsies were obtained from 64 individuals with LSP undergoing spinal surgery. Eight participants performed an acute bout of machine-based lumbar extension resistance exercise preoperatively. Gene expression for 42 genes associated with adipogenic/metabolic, atrophic, fibrogenic, inflammatory, and myogenic pathways was measured, and differential expression between exercised and non-exercised groups was evaluated for (a) the full cohort, and (b) an age, gender, acuity, and etiology matched sub-cohort. Principal components analyses were used to identify gene expression clustering across clinical phenotypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The exercised cohort demonstrated upregulation of inflammatory gene IL1B, inhibition of extracellular matrix components (increased MMP3&9, decreased TIMP1&3, COL1A1) and metabolic/adipogenic genes (FABP4, PPARD, WNT10B), and downregulation of myogenic (MYOD, ANKRD2B) and atrophic (FOXO3) genes compared to the non-exercised cohort, with similar patterns in the matched sub-analysis. There were no clinical phenotypes significantly associated with gene expression profiles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>An acute bout of moderate-high intensity resistance exercise did not result in upregulation of myogenic genes in individuals with LSP. The response was characterized by mixed metabolic and fibrotic gene expression, upregulation of inflammation, and downregulation of myogenesis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136069122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Garrett W. D. Easson, Alireza Savadipour, Christian Gonzalez, Farshid Guilak, Simon Y. Tang
Background
The ion channel transient receptor potential vanilloid 4 (TRPV4) critically transduces mechanical forces in the IVD, and its inhibition can prevent IVD degeneration due to static overloading. However, it remains unknown whether different modes of loading signals through TRPV4 to regulate the expression of inflammatory cytokines. We hypothesized that TRPV4 signaling is essential during static and dynamic loading to mediate homeostasis and mechanotransduction.
Methods
Mouse functional spine units were isolated and either cyclically compressed for 5 days (1 Hz, 1 h, 10% strain) or statically compressed (24 h, 0.2 MPa). Conditioned media were monitored at 6 h, 24 h, 2 days, and 5 days, with and without TRPV4 inhibition. Effects of TRPV4 activation was also evaluated without loading. The media was analyzed for a panel of 44 cytokines using a microbead array and then a correlative network was constructed to explore the regulatory relationships during loading and TRPV4 inhibition. After the loading regimen, the IVDs were evaluated histologically for degeneration.
Results
Activation of TRPV4 led to an increase interleukin-6 (IL-6) family of cytokines (IL-6, IL-11, IL-16, and leukemia inhibitory factor [LIF]) and decreased the T-cell (CCL3, CCL4, CCL17, CCL20, CCL22, and CXCL10) and monocyte (CCL2 and CCL12) recruiting chemokines by the IVD. Dynamic and static loading each provoked unique chemokine correlation networks. The inhibition of TRPV4 during dynamic loading dysregulated the relationship between LIF and other cytokines, while the inhibition of TRPV4 during static loading disrupted the connectivity of IL-16 and VEGFA.
Conclusions
We demonstrated that TRPV4 critically mediates the cytokine production following dynamic and static loading. The activation of TRPV4 upregulated a diverse set of cytokines that may suppress the chemotaxis of T-cells and monocytes, implicating the role of TRPV4 in maintaining the immune privilege of healthy IVD.
{"title":"TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc","authors":"Garrett W. D. Easson, Alireza Savadipour, Christian Gonzalez, Farshid Guilak, Simon Y. Tang","doi":"10.1002/jsp2.1282","DOIUrl":"10.1002/jsp2.1282","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The ion channel transient receptor potential vanilloid 4 (TRPV4) critically transduces mechanical forces in the IVD, and its inhibition can prevent IVD degeneration due to static overloading. However, it remains unknown whether different modes of loading signals through TRPV4 to regulate the expression of inflammatory cytokines. We hypothesized that TRPV4 signaling is essential during static and dynamic loading to mediate homeostasis and mechanotransduction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mouse functional spine units were isolated and either cyclically compressed for 5 days (1 Hz, 1 h, 10% strain) or statically compressed (24 h, 0.2 MPa). Conditioned media were monitored at 6 h, 24 h, 2 days, and 5 days, with and without TRPV4 inhibition. Effects of TRPV4 activation was also evaluated without loading. The media was analyzed for a panel of 44 cytokines using a microbead array and then a correlative network was constructed to explore the regulatory relationships during loading and TRPV4 inhibition. After the loading regimen, the IVDs were evaluated histologically for degeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Activation of TRPV4 led to an increase interleukin-6 (IL-6) family of cytokines (IL-6, IL-11, IL-16, and leukemia inhibitory factor [LIF]) and decreased the T-cell (CCL3, CCL4, CCL17, CCL20, CCL22, and CXCL10) and monocyte (CCL2 and CCL12) recruiting chemokines by the IVD. Dynamic and static loading each provoked unique chemokine correlation networks. The inhibition of TRPV4 during dynamic loading dysregulated the relationship between LIF and other cytokines, while the inhibition of TRPV4 during static loading disrupted the connectivity of IL-16 and VEGFA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We demonstrated that TRPV4 critically mediates the cytokine production following dynamic and static loading. The activation of TRPV4 upregulated a diverse set of cytokines that may suppress the chemotaxis of T-cells and monocytes, implicating the role of TRPV4 in maintaining the immune privilege of healthy IVD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"6 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1282","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136317401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew Fainor, Brianna S. Orozco, Victoria G. Muir, Sonal Mahindroo, Sachin Gupta, Robert L. Mauck, Jason A. Burdick, Harvey E. Smith, Sarah E. Gullbrand
Background
Vertebral endplate sclerosis and facet osteoarthritis have been documented in animals and humans. However, it is unclear how these adjacent pathologies engage in crosstalk with the intervertebral disc. This study sought to elucidate this crosstalk by assessing each compartment individually in response to acute disc injury.
Methods
Eleven New Zealand White rabbits underwent annular disc puncture using a 16G or 21G needle. At 4 and 10 weeks, individual compartments of the motion segment were analyzed. Discs underwent T1 relaxation mapping with MRI contrast agent gadodiamide as well T2 mapping. Both discs and facets underwent mechanical testing via vertebra—disc—vertebra tension-compression creep testing and indentation testing, respectively. Endplate bone density was quantified via μCT. Discs and facets were sectioned and stained for histology scoring.
Results
Intervertebral discs became more degenerative with increasing needle diameter and time post-puncture. Bone density also increased in endplates adjacent to both 21G and 16G punctured discs leading to reduced gadodiamide transport at 10 weeks. The facet joints, however, did not follow this same trend. Facets adjacent to 16G punctured discs were less degenerative than facets adjacent to 21G punctured discs at 10 weeks. 16G facets were more degenerative at 4 weeks than at 10, suggesting the cartilage had recovered. The formation of severe disc osteophytes in 16G punctured discs between 4 and 10 weeks likely offloaded the facet cartilage, leading to the recovery observed.
Conclusions
Overall, this study supports that degeneration spans the whole spinal motion segment following disc injury. Vertebral endplate thickening occurred in response to disc injury, which limited the diffusion of small molecules into the disc. This work also suggests that altered disc mechanics can induce facet degeneration, and that extreme bony remodeling adjacent to the disc may promote facet cartilage recovery through offloading of the articular cartilage.
{"title":"Mechanical crosstalk between the intervertebral disc, facet joints, and vertebral endplate following acute disc injury in a rabbit model","authors":"Matthew Fainor, Brianna S. Orozco, Victoria G. Muir, Sonal Mahindroo, Sachin Gupta, Robert L. Mauck, Jason A. Burdick, Harvey E. Smith, Sarah E. Gullbrand","doi":"10.1002/jsp2.1287","DOIUrl":"10.1002/jsp2.1287","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Vertebral endplate sclerosis and facet osteoarthritis have been documented in animals and humans. However, it is unclear how these adjacent pathologies engage in crosstalk with the intervertebral disc. This study sought to elucidate this crosstalk by assessing each compartment individually in response to acute disc injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Eleven New Zealand White rabbits underwent annular disc puncture using a 16G or 21G needle. At 4 and 10 weeks, individual compartments of the motion segment were analyzed. Discs underwent <i>T</i><sub>1</sub> relaxation mapping with MRI contrast agent gadodiamide as well <i>T</i><sub>2</sub> mapping. Both discs and facets underwent mechanical testing via vertebra—disc—vertebra tension-compression creep testing and indentation testing, respectively. Endplate bone density was quantified via μCT. Discs and facets were sectioned and stained for histology scoring.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Intervertebral discs became more degenerative with increasing needle diameter and time post-puncture. Bone density also increased in endplates adjacent to both 21G and 16G punctured discs leading to reduced gadodiamide transport at 10 weeks. The facet joints, however, did not follow this same trend. Facets adjacent to 16G punctured discs were less degenerative than facets adjacent to 21G punctured discs at 10 weeks. 16G facets were more degenerative at 4 weeks than at 10, suggesting the cartilage had recovered. The formation of severe disc osteophytes in 16G punctured discs between 4 and 10 weeks likely offloaded the facet cartilage, leading to the recovery observed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Overall, this study supports that degeneration spans the whole spinal motion segment following disc injury. Vertebral endplate thickening occurred in response to disc injury, which limited the diffusion of small molecules into the disc. This work also suggests that altered disc mechanics can induce facet degeneration, and that extreme bony remodeling adjacent to the disc may promote facet cartilage recovery through offloading of the articular cartilage.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"6 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1287","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135267510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jae-Young Jung, Mohamed Habib, Luke J. Morrissette, Shannon C. Timmons, Tristan Maerz, Aaron J. Fields
Background
Intervertebral disc degeneration is associated with low back pain, which is a leading cause of disability. While the precise causes of disc degeneration are unknown, inadequate nutrient and metabolite transport through the cartilage endplate (CEP) may be one important factor. Prior work shows that CEP transport properties depend on the porosity of the CEP matrix, but little is known about the role of CEP characteristics that could influence transport properties independently from porosity. Here, we show that CEP transport properties depend on the extent of non-enzymatic glycation of the CEP matrix.
Methods and Results
Using in vitro ribosylation to induce non-enzymatic glycation and promote the formation of advanced glycation end products, we found that ribosylation reduced glucose partition coefficients in human cadaveric lumbar CEP tissues by 10.7%, on average, compared with donor- and site-matched CEP tissues that did not undergo ribosylation (p = 0.04). These reductions in glucose uptake were observed in the absence of differences in CEP porosity (p = 0.89) or in the amounts of sulfated glycosaminoglycans (sGAGs, p = 0.47) or collagen (p = 0.61). To investigate whether ribosylation altered electrostatic interactions between fixed charges on the sGAG molecules and the mobile free ions, we measured the charge density in the CEP matrix using equilibrium partitioning of a cationic contrast agent using micro-computed tomography. After contrast enhancement, mean X-ray attenuation was 11.9% lower in the CEP tissues that had undergone ribosylation (p = 0.02), implying the CEP matrix was less negatively charged.
Conclusions
Taken together, these findings indicate that non-enzymatic glycation negatively impacts glucose transport in the CEP independent of matrix porosity or sGAG content and that the effects may be mediated by alterations to matrix charge density.
{"title":"Non-enzymatic glycation reduces glucose transport in the human cartilage endplate independently of matrix porosity or proteoglycan content","authors":"Jae-Young Jung, Mohamed Habib, Luke J. Morrissette, Shannon C. Timmons, Tristan Maerz, Aaron J. Fields","doi":"10.1002/jsp2.1297","DOIUrl":"10.1002/jsp2.1297","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intervertebral disc degeneration is associated with low back pain, which is a leading cause of disability. While the precise causes of disc degeneration are unknown, inadequate nutrient and metabolite transport through the cartilage endplate (CEP) may be one important factor. Prior work shows that CEP transport properties depend on the porosity of the CEP matrix, but little is known about the role of CEP characteristics that could influence transport properties independently from porosity. Here, we show that CEP transport properties depend on the extent of non-enzymatic glycation of the CEP matrix.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>Using in vitro ribosylation to induce non-enzymatic glycation and promote the formation of advanced glycation end products, we found that ribosylation reduced glucose partition coefficients in human cadaveric lumbar CEP tissues by 10.7%, on average, compared with donor- and site-matched CEP tissues that did not undergo ribosylation (<i>p</i> = 0.04). These reductions in glucose uptake were observed in the absence of differences in CEP porosity (<i>p</i> = 0.89) or in the amounts of sulfated glycosaminoglycans (sGAGs, <i>p</i> = 0.47) or collagen (<i>p</i> = 0.61). To investigate whether ribosylation altered electrostatic interactions between fixed charges on the sGAG molecules and the mobile free ions, we measured the charge density in the CEP matrix using equilibrium partitioning of a cationic contrast agent using micro-computed tomography. After contrast enhancement, mean X-ray attenuation was 11.9% lower in the CEP tissues that had undergone ribosylation (<i>p</i> = 0.02), implying the CEP matrix was less negatively charged.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Taken together, these findings indicate that non-enzymatic glycation negatively impacts glucose transport in the CEP independent of matrix porosity or sGAG content and that the effects may be mediated by alterations to matrix charge density.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135267856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katherine B. Crump, Ahmad Alminnawi, Paola Bermudez-Lekerika, Roger Compte, Francesco Gualdi, Terence McSweeney, Estefano Muñoz-Moya, Andrea Nüesch, Liesbet Geris, Stefan Dudli, Jaro Karppinen, Jérôme Noailly, Christine Le Maitre, Benjamin Gantenbein
The cartilaginous endplates (CEP) are key components of the intervertebral disc (IVD) necessary for sustaining the nutrition of the disc while distributing mechanical loads and preventing the disc from bulging into the adjacent vertebral body. The size, shape, and composition of the CEP are essential in maintaining its function, and degeneration of the CEP is considered a contributor to early IVD degeneration. In addition, the CEP is implicated in Modic changes, which are often associated with low back pain. This review aims to tackle the current knowledge of the CEP regarding its structure, composition, permeability, and mechanical role in a healthy disc, how they change with degeneration, and how they connect to IVD degeneration and low back pain. Additionally, the authors suggest a standardized naming convention regarding the CEP and bony endplate and suggest avoiding the term vertebral endplate. Currently, there is limited data on the CEP itself as reported data is often a combination of CEP and bony endplate, or the CEP is considered as articular cartilage. However, it is clear the CEP is a unique tissue type that differs from articular cartilage, bony endplate, and other IVD tissues. Thus, future research should investigate the CEP separately to fully understand its role in healthy and degenerated IVDs. Further, most IVD regeneration therapies in development failed to address, or even considered the CEP, despite its key role in nutrition and mechanical stability within the IVD. Thus, the CEP should be considered and potentially targeted for future sustainable treatments.
{"title":"Cartilaginous endplates: A comprehensive review on a neglected structure in intervertebral disc research","authors":"Katherine B. Crump, Ahmad Alminnawi, Paola Bermudez-Lekerika, Roger Compte, Francesco Gualdi, Terence McSweeney, Estefano Muñoz-Moya, Andrea Nüesch, Liesbet Geris, Stefan Dudli, Jaro Karppinen, Jérôme Noailly, Christine Le Maitre, Benjamin Gantenbein","doi":"10.1002/jsp2.1294","DOIUrl":"10.1002/jsp2.1294","url":null,"abstract":"<p>The cartilaginous endplates (CEP) are key components of the intervertebral disc (IVD) necessary for sustaining the nutrition of the disc while distributing mechanical loads and preventing the disc from bulging into the adjacent vertebral body. The size, shape, and composition of the CEP are essential in maintaining its function, and degeneration of the CEP is considered a contributor to early IVD degeneration. In addition, the CEP is implicated in Modic changes, which are often associated with low back pain. This review aims to tackle the current knowledge of the CEP regarding its structure, composition, permeability, and mechanical role in a healthy disc, how they change with degeneration, and how they connect to IVD degeneration and low back pain. Additionally, the authors suggest a standardized naming convention regarding the CEP and bony endplate and suggest avoiding the term vertebral endplate. Currently, there is limited data on the CEP itself as reported data is often a combination of CEP and bony endplate, or the CEP is considered as articular cartilage. However, it is clear the CEP is a unique tissue type that differs from articular cartilage, bony endplate, and other IVD tissues. Thus, future research should investigate the CEP separately to fully understand its role in healthy and degenerated IVDs. Further, most IVD regeneration therapies in development failed to address, or even considered the CEP, despite its key role in nutrition and mechanical stability within the IVD. Thus, the CEP should be considered and potentially targeted for future sustainable treatments.</p>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"6 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1294","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135512642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jesse Shen, Nathalie Samson, Jérôme Lamontagne-Proulx, Denis Soulet, Yves Tremblay, Marc Bazin, Charlène Nadeau, Sarah Bouchard, Jean-Paul Praud, Stefan Parent
Background
The evolution and treatment of lung alterations related to congenital spine and chest wall deformities (CWD) are poorly understood. Most animal models of CWD created postnatally were not evaluated for respiratory function. The goal of our study was to evaluate the effects of a CWD induced in utero on lung growth and function in an ovine model.
Methods
A CWD was induced in utero at 70–75 days of gestation in 14 ovine fetuses by resection of the 7th and 8th left ribs. Each non-operated twin fetus was taken as control. Respiratory mechanics was studied postnatally in the first week and at 1, 2, and 3 months. Post-mortem respiratory mechanics and lung histomorphometry were also assessed at 3 months.
Results
Eight out of 14 CWD lambs (57%) and 14 control lambs survived the postnatal period. One severe and five mild deformities were induced. At birth, inspiratory capacity (25 vs. 32 mL/kg in controls), and dynamic (1.4 vs. 1.8 mL/cmH2O/kg), and static (2.0 vs. 2.5 mL/cmH2O/kg) respiratory system compliances were decreased in CWD lambs. Apart from a slight decrease in inspiratory capacity at 1 month of life, no other differences were observed in respiratory mechanics measured in vivo thereafter. Postmortem measurements found a significant decrease in lung compliance—for each lung and for both lungs taken together—in CWD lambs. No differences in lung histology were detected at 3 months in CWD animals compared to controls.
Conclusions
Our study is the first to assess the effects of a prenatally induced CWD on lung development and function from birth to 3 months in an ovine model. Our results show no significant differences in lung histomorphometry at 3 months in CWD lambs compared to controls. Resolution at 1 month of the alterations in respiratory mechanics present at birth may be related to the challenge in inducing severe deformities.
{"title":"Ovine model of congenital chest wall and spine deformity: From birth to 3 months follow-up","authors":"Jesse Shen, Nathalie Samson, Jérôme Lamontagne-Proulx, Denis Soulet, Yves Tremblay, Marc Bazin, Charlène Nadeau, Sarah Bouchard, Jean-Paul Praud, Stefan Parent","doi":"10.1002/jsp2.1295","DOIUrl":"10.1002/jsp2.1295","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The evolution and treatment of lung alterations related to congenital spine and chest wall deformities (CWD) are poorly understood. Most animal models of CWD created postnatally were not evaluated for respiratory function. The goal of our study was to evaluate the effects of a CWD induced in utero on lung growth and function in an ovine model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A CWD was induced in utero at 70–75 days of gestation in 14 ovine fetuses by resection of the 7th and 8th left ribs. Each non-operated twin fetus was taken as control. Respiratory mechanics was studied postnatally in the first week and at 1, 2, and 3 months. Post-mortem respiratory mechanics and lung histomorphometry were also assessed at 3 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eight out of 14 CWD lambs (57%) and 14 control lambs survived the postnatal period. One severe and five mild deformities were induced. At birth, inspiratory capacity (25 vs. 32 mL/kg in controls), and dynamic (1.4 vs. 1.8 mL/cmH<sub>2</sub>O/kg), and static (2.0 vs. 2.5 mL/cmH<sub>2</sub>O/kg) respiratory system compliances were decreased in CWD lambs. Apart from a slight decrease in inspiratory capacity at 1 month of life, no other differences were observed in respiratory mechanics measured in vivo thereafter. Postmortem measurements found a significant decrease in lung compliance—for each lung and for both lungs taken together—in CWD lambs. No differences in lung histology were detected at 3 months in CWD animals compared to controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study is the first to assess the effects of a prenatally induced CWD on lung development and function from birth to 3 months in an ovine model. Our results show no significant differences in lung histomorphometry at 3 months in CWD lambs compared to controls. Resolution at 1 month of the alterations in respiratory mechanics present at birth may be related to the challenge in inducing severe deformities.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135884484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M1 macrophages (Mφs) are involved in osteogenic differentiation of ligamentum flavum (LF) cells and play an important role in heterotopic ossification. However, the mechanism by which M1 Mφs influence osteogenic differentiation of LF cells has not been studied.
Methods
The effect of conditioned medium including secretions of M1 Mφs (CM-M1) on LF cells was analyzed by GeneChip profiling and ingenuity pathway analysis (IPA). THP-1 cells were polarized into M1 Mφs and CM-M1 was used to induce LF cells. In addition, LF cells were induced by CM-M1 in the presence of cyclooxygenase 2 (COX-2) inhibitors or oncostatin M (OSM)-neutralizing antibodies. Based on the presence of OSM, knockout of OSMR or GP130 receptors, or addition of the Janus kinase 2 (JAK2) inhibitor AZD1480 or signal transducer and activator of transcription 3 (STAT3) inhibitor Stattic were examined for effects on osteogenic differentiation of LF cells. OSM secretion was quantified by ELISA, while qPCR and western blot were used to evaluate expression of osteogenic genes and receptor and signaling pathway-related proteins, respectively.
Results
GeneChip and IPA results indicate that the OSM signaling pathway and its downstream signaling molecules JAK2 and STAT3 are significantly activated. ELISA results indicate that OSM is highly expressed in cells treated with CM-M1 and lowly expressed in cells treated with CM-M1 and a COX-2 inhibitor. Besides, CM-M1 induces osteogenic differentiation of LF cells, which is weakened when COX-2 inhibitors or OSM-neutralizing antibody are added to it. Recombinant OSM could induce osteogenic differentiation of LF cells and upregulate expression of OSMR, GP130, phosphorylated (P)-JAK2, and P-STAT3. Upon knockdown of OSMR or GP130, or the addition of AZD1480 or Stattic, P-JAK2 and P-STAT3 expression were decreased and osteogenic differentiation was reduced.
Conclusion
M1 Mφ-derived OSM induces osteogenic differentiation of LF cells and the JAK2/STAT3 signaling pathway plays an important role.
{"title":"M1 macrophage-derived oncostatin M induces osteogenic differentiation of ligamentum flavum cells through the JAK2/STAT3 pathway","authors":"Jun Yang, Guanghui Chen, Tianqi Fan, Xiaochen Qu","doi":"10.1002/jsp2.1290","DOIUrl":"10.1002/jsp2.1290","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>M1 macrophages (Mφs) are involved in osteogenic differentiation of ligamentum flavum (LF) cells and play an important role in heterotopic ossification. However, the mechanism by which M1 Mφs influence osteogenic differentiation of LF cells has not been studied.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The effect of conditioned medium including secretions of M1 Mφs (CM-M1) on LF cells was analyzed by GeneChip profiling and ingenuity pathway analysis (IPA). THP-1 cells were polarized into M1 Mφs and CM-M1 was used to induce LF cells. In addition, LF cells were induced by CM-M1 in the presence of cyclooxygenase 2 (COX-2) inhibitors or oncostatin M (OSM)-neutralizing antibodies. Based on the presence of OSM, knockout of OSMR or GP130 receptors, or addition of the Janus kinase 2 (JAK2) inhibitor AZD1480 or signal transducer and activator of transcription 3 (STAT3) inhibitor Stattic were examined for effects on osteogenic differentiation of LF cells. OSM secretion was quantified by ELISA, while qPCR and western blot were used to evaluate expression of osteogenic genes and receptor and signaling pathway-related proteins, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GeneChip and IPA results indicate that the OSM signaling pathway and its downstream signaling molecules JAK2 and STAT3 are significantly activated. ELISA results indicate that OSM is highly expressed in cells treated with CM-M1 and lowly expressed in cells treated with CM-M1 and a COX-2 inhibitor. Besides, CM-M1 induces osteogenic differentiation of LF cells, which is weakened when COX-2 inhibitors or OSM-neutralizing antibody are added to it. Recombinant OSM could induce osteogenic differentiation of LF cells and upregulate expression of OSMR, GP130, phosphorylated (P)-JAK2, and P-STAT3. Upon knockdown of OSMR or GP130, or the addition of AZD1480 or Stattic, P-JAK2 and P-STAT3 expression were decreased and osteogenic differentiation was reduced.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>M1 Mφ-derived OSM induces osteogenic differentiation of LF cells and the JAK2/STAT3 signaling pathway plays an important role.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1290","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135883580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Minhao Zhou, Alekos A. Theologis, Grace D. O’Connell
Lumbar intervertebral disc herniation, as a leading cause of low back pain, productivity loss, and disability, is a common musculoskeletal disorder that results in significant socioeconomic burdens. Despite extensive clinical and basic scientific research efforts, herniation etiopathogenesis, particularly its initiation and progression, is not well understood. Understanding herniation etiopathogenesis is essential for developing effective preventive measures and therapeutic interventions. Thus, this review seeks to provide a thorough overview of the advances in herniation-oriented research, with a discussion on ongoing challenges and potential future directions for clinical, translational, and basic scientific investigations to facilitate innovative interdisciplinary research aimed at understanding herniation etiopathogenesis. Specifically, risk factors for herniation are identified and summarized, including familial predisposition, obesity, diabetes mellitus, smoking tobacco, selected cardiovascular diseases, disc degeneration, and occupational risks. Basic scientific experimental and computational research that aims to understand the link between excessive mechanical load, catabolic tissue remodeling due to inflammation or insufficient nutrient supply, and herniation, are also reviewed. Potential future directions to address the current challenges in herniation-oriented research are explored by combining known progressive development in existing research techniques with ongoing technological advances. More research on the relationship between occupational risk factors and herniation, as well as the relationship between degeneration and herniation, is needed to develop preventive measures for working-age individuals. Notably, researchers should explore using or modifying existing degeneration animal models to study herniation etiopathogenesis, as such models may allow for a better understanding of how to prevent mild-to-moderately degenerated discs from herniating.
{"title":"Understanding the etiopathogenesis of lumbar intervertebral disc herniation: From clinical evidence to basic scientific research","authors":"Minhao Zhou, Alekos A. Theologis, Grace D. O’Connell","doi":"10.1002/jsp2.1289","DOIUrl":"10.1002/jsp2.1289","url":null,"abstract":"<p>Lumbar intervertebral disc herniation, as a leading cause of low back pain, productivity loss, and disability, is a common musculoskeletal disorder that results in significant socioeconomic burdens. Despite extensive clinical and basic scientific research efforts, herniation etiopathogenesis, particularly its initiation and progression, is not well understood. Understanding herniation etiopathogenesis is essential for developing effective preventive measures and therapeutic interventions. Thus, this review seeks to provide a thorough overview of the advances in herniation-oriented research, with a discussion on ongoing challenges and potential future directions for clinical, translational, and basic scientific investigations to facilitate innovative interdisciplinary research aimed at understanding herniation etiopathogenesis. Specifically, risk factors for herniation are identified and summarized, including familial predisposition, obesity, diabetes mellitus, smoking tobacco, selected cardiovascular diseases, disc degeneration, and occupational risks. Basic scientific experimental and computational research that aims to understand the link between excessive mechanical load, catabolic tissue remodeling due to inflammation or insufficient nutrient supply, and herniation, are also reviewed. Potential future directions to address the current challenges in herniation-oriented research are explored by combining known progressive development in existing research techniques with ongoing technological advances. More research on the relationship between occupational risk factors and herniation, as well as the relationship between degeneration and herniation, is needed to develop preventive measures for working-age individuals. Notably, researchers should explore using or modifying existing degeneration animal models to study herniation etiopathogenesis, as such models may allow for a better understanding of how to prevent mild-to-moderately degenerated discs from herniating.</p>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135883422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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